1. Field of the Invention
The present invention relates generally to the use of antibodies as biopharmacological buffers for regulating drug concentration, half-life, bioactivity and/or bioavailability. More specifically, invention embodiments as disclosed herein relate to regionally administering a drug and a specific anti-drug antibody, to treat a disease or disorder in a selected body compartment.
2. Description of the Related Art
Despite the fact that a vast number of diseases in humans and animals are characterized by adverse pathophysiological effects that are localized to particular sites, tissues or organs in an afflicted individual, the majority of therapeutic treatment regimens for such conditions involve systemic or global administration of a therapeutic drug, for example, via oral or intravenous routes. (See, e.g., Rang, H. P. et al. (Eds.), Pharmacology, 2003 Churchill Livingstone, New York, Ch. 7, pp. 91-105.) Consequently, pharmacologic or suprapharmacologic levels of a drug are often achieved in clinically irrelevant, inappropriate and/or undesirable anatomical locations within the recipient (including circulating plasma concentrations), as the by-product of efforts to attain a therapeutically effective level of such drug at a relatively restricted site. Drug clearance and degradation activities in the body often necessitate repeated administration of the drug, which can often lead to recurring wide fluctuations in the actual circulating drug concentration.
For instance, chemotherapy plays a significant role in the current treatment regime for young children with brain tumors because radiation often leads to developmental delay and neuroendocrine deficiencies in these patients (Zalutsky, 2004 Br. J. Canc. 90:1469). Tumors of the central nervous system (CNS) represent the second most frequent malignancy in children under the age of 15 years (Heideman et al., 1997 Cancer 80:497). Forty-five percent of these children will die of their disease, but not well recorded is the morbidity of the survivors, a result of the motor and intellectual deficits associated with the aggressive chemotherapeutic protocols currently used, as well as with the tumors themselves. Given that many brain-intrinsic neoplasms are characterized by relentless tumor cell infiltration of normal brain parenchyma, strategies for targeting therapeutic agents to tumors often feature drugs having diffusive properties, in order for them to reach invading tumor cell clusters that migrate along vascular clefts and axonal pathways (Merlo et al., 2003 Acta Neurochir. Suppl. 88:83).
Despite their widespread application, the use of chemotherapeutic agents in treatment of solid tumors involving the brain parenchyma has not been very successful (Castro et al., 2003 Pharmacol. Ther. 98:71). Tumors of the CNS are usually slow-growing, so treatment regimens with the cell cycle-inhibiting drugs currently available typically call for these agents to remain at an effective concentration for a lengthy period of time. Achieving this effective drug concentration at the tumor site for such time periods represents a major technical obstacle (Blasberg, 1975 J. Pharmacol. Exp. Ther. 195:73). Further drawbacks to the use of chemotherapy are the development of chemoresistant cells, and inadequate drug delivery methods (Castro et al., 2003). Also troubling is that although anticancer drugs may kill tumor cells, useful dosage ranges for such drugs are limited by global drug toxicity to hematopoietic cells, leading to undesirable myelosuppression.
The problem of effective drug delivery to a restricted site, whether in the CNS or elsewhere, is compounded by a variety of factors such as drug absorption and stability in vivo (e.g., Bialer, 1992 Clin. Pharmacokinet. 22:11), physiological drug clearance and elimination mechanisms (e.g., Anderson et al., 1994 Clin. Pharmacokinet. 27:191), drug inactivation by binding to plasma proteins in the circulation and/or to proteins in interstitial fluids (e.g., Koch-Weser et al., 1976 N. Engl. J. Med. 294:311; Kremer et al., 1988 Pharmacol. Rev. 40:1; Sparreboom et al., 2001 Neth. J. Med. 59:196), and drug accessibility to specific drug target molecules in affected cells and tissues (e.g., Begley, 2004 Pharmacol. Therapeut. 104:29). In particular, impediments to the effective delivery of a systemically administered drug to a restricted site arise as a result of physical, anatomical, pharmacokinetic and/or physiological barriers that separate a number of body compartments.
The CNS, for example, is rendered a discrete body compartment by the blood-brain barrier (BBB; e.g., Begley, 2004). As other examples, the eye, the joint capsule including the relatively avascular articular cartilage (e.g., WO 01/20018 and references cited therein), the pleural sac, the peritoneum and the pericardium represent additional body compartments into which effective, localized drug delivery can be problematic.
Multiple strategies have been devised in efforts to deliver effective amounts of therapeutic drugs to such body compartments using global administration such as oral or intravenous routes. These strategies include formulation of drugs for delivery as polymers, gels, microcarriers, liposomes, aggregates, affinity-targeted conjugates, inhalants, microspheres, viral vectors, iontophoresis agents, chemically modified derivatives, sustained release formulations, and other formats (e.g., Cheng et al., 2004 Mol. Pharm. 1:183; Goyal et al., 2005 Acta Pharm. 55:1; Agu et al., 2004 Endocr. Res. 30:455; Siashin et al., 2003 Invest. Ophthalmol. Vis. Sci. 44:4989; Goskonda et al., 2001 J. Pharm. Sci. 90:12; Pettit et al., 1998 Trends Biotechnol. 16:343; Groothuis et al., 1997 J. Neurovirol. 3:387; Langner et al., 200 Cell. Molec. Biol. Lett. 5:433; Ohning 1995 Neonatal Netw. 14:7; Ohning 1995 Neonatal Netw. 14:15; Sood et al., 2003 Int J. Pharmaceut. 261:27; Olivier, 2005 NeuroRx 2:108). With regard to specific delivery to a desired body compartment, however, these approaches are plagued by one or more shortcomings that include, for example, difficulties in achieving desired local drug levels, difficulties in maintaining desired local drug levels over time, non-specific passive diffusion and/or active transport of drug to undesired compartments, premature clearance and/or elimination of the drug, adverse collateral effects on adjacent tissues that result from drug delivery, inadequate accessibility of the compartment to drug, unsuitability of the active ingredient to the delivery modification, and other problems. (e.g., Baker, 1987 Controlled Release of Biologically Active Agents, John Wiley & Sons, NY; Dash et al., 1998 J. Pharmacol. Toxicol. Meths. 40:1; Huang et al., 2001 J. Control Release 73:121; Gordon et al., 1995 Cancer 75:2169; Lotem et al., 2000 Arch. Dermatol. 136:1475; Lyass et al., 2000 Cancer 89:1037.
In certain cases, alternative attempts to achieve specific and effective delivery of a therapeutic drug to a body compartment have involved direct injection of the drug to the afflicted area (Rang, H. P. et al. (Eds.), In Pharmacology, 2003, pp. 91-105; Begley, 2004 Pharmacol. Therap. 104:29; Anderson et al., 1994 Clin. Pharmacokinet. 27:191; Dedrick et al., 1978 Canc. Treat. Rep. 62:1; Clay et al., 1992 Hematol. Oncol. Clin. N. Am. 6:915; Oh et al., 1995 Pharm. Res. 12:433; Hopkins et al., 1993 J. Drug Target 1:175). Such approaches have, however, been plagued by issues of safety, efficacy, cost, convenience and other factors, and not all body compartments are amenable to multiple direct interventions over a therapeutic timeframe. For example, direct injection to the CNS is accompanied by risks associated with irreversible damage to CNS tissue and the potential for microbial infection associated with repeated access to a site, and the CNS as well as other compartments may only be directly accessible through skill- and labor-intensive surgical procedures. Additionally, therapeutic drugs administered directly to the CNS may not persist there, being released instead from the CNS to the general circulation as a consequence of the directional bulk flow of CNS interstitial fluid (e.g., Bergsneider 2001 Neurosurg. Clin. N. Amer. 12:631). As another example, cancer therapy involving direct intraperitoneal injection of an anti-cancer drug has resulted in leakage of significant and potentially toxic levels of the drug out of the peritoneal compartment and into the general circulation (e.g., Balthasar et al., 1994 J. Pharmacol. Exp. Ther. 268:734; Balthasar et al., 1996 J. Pharm. Sci. 85:1035; Lobo et al., 2003 J. Pharm. Sci. 92:1665).
Clearly there is a need for improved methods and compositions for administering and delivering drugs without repeated direct intervention, and in a manner that permits maintenance of a desired level of the drug in a selected body compartment. New approaches would also desirably avoid unwanted consequences of non-specific drug delivery, such as wide fluctuations in local drug concentrations or other clinically detrimental effects. The present invention fulfills such needs and offers other related advantages.